Principal Investigator/Program Director (Last, First, Middle): Morris, Martha Clare This R01 application, entitled ?Epidemiological Neuropathologic Study of Metallomics and Alzheimer's Disease? is a new submission in response to PAR-15-356. By the year 2050 it is projected that there will be 13.5 million Americans with AD at a cost of $1.1 trillion. Recent large-scale phase III clinical trials of drugs targeting known pathways involved in AD have either failed to benefit patients, or indicated very limited efficacy. Whereas beta amyloid (A?) may be a principal driver of the disease, multiple failed clinical trials of drugs targeting this peptide suggest that A? is a poor therapeutic target for AD. Iron accumulates in the affected brain regions in AD, and has the potential to drive disease progression by causing oxidative stress and the aggregation of A? and tau, and is thus an alternate therapeutic target. In previous studies we showed that the iron burden of the brain (as reflected in CSF ferritin levels) has an effect on multiple longitudinal outcomes of AD comparable in magnitude to more established factors in the disease: tau and A?. We have preliminary data showing a strong positive association between brain iron levels and neurofibrillary tangle pathology, particularly in APOE-?4 carriers. There has not been a systematic, well powered, and detailed exploration of brain iron levels in AD. Here, we propose to use a large, well-characterized post mortem cohort study, the Rush Memory and Aging Project, to investigate brain iron concentrations in AD of 680 autopsied brains using advanced techniques. We will investigate the impact of the iron load of the brain on AD neuropathology and cognitive clinical history; investigate potential causes of iron accumulation in AD including diet, and genetic factors; and explore neurochemical mechanisms of iron elevation using advanced proteomics and metalloproteomics. This foundational study has the potential to (1) establish whether iron concentrations are related to the disease, (2) validate iron as a therapeutic target for AD, (3) discover new molecular targets for lowering iron, (4) identify whether diet influences brain iron levels and AD risk, and (6) determine whether genetic factors, including APOE allele variation, impacts on iron in AD. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page